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Various factors can contribute to superior diffusion profiles. In this study, we find that size, charge, and morphology play important roles. Further, we report an analysis that demonstrates the subtle effects that small chemical changes can have on whole-particle properties and the corresponding in vivo readouts. We use computational modeling to reveal previously unconsidered design criteria and hypothesize that cargo-templating considerations appear sufficient to connect differences in the internal structural organization to observed whole-particle properties. Collectively, computational and experimental findings work in synergy to deepen our molecular-level investigative capabilities to design and optimize nucleic acid delivery systems.<\/jats:p>","DOI":"10.1021\/acs.biomac.5c02711","type":"journal-article","created":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T08:01:41Z","timestamp":1790496101000},"page":"6299-6310","source":"Crossref","is-referenced-by-count":0,"title":["Revealing Nanomedicine Design Principles for Efficient siRNA Delivery to the Central Nervous System"],"prefix":"10.1021","volume":"27","author":[{"given":"Zhe","family":"Tan","sequence":"first","affiliation":[{"name":"Eli Lilly and Company , , , ,","place":["Boston, Massachusetts, United States, 02210"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3756-0007","authenticated-orcid":true,"given":"Supreet","family":"Kaur","sequence":"additional","affiliation":[{"name":"Eli Lilly and Company , , , ,","place":["Boston, Massachusetts, United States, 02210"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8485-8722","authenticated-orcid":true,"given":"Ritam","family":"Das","sequence":"additional","affiliation":[{"name":"University of Massachusetts , , , ,","place":["Amherst, Massachusetts, United States, 01003"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saeideh","family":"Nozohouri","sequence":"additional","affiliation":[{"name":"Eli Lilly and Company , , , ,","place":["Boston, Massachusetts, United States, 02210"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harmon","family":"Johnson","sequence":"additional","affiliation":[{"name":"Eli Lilly and Company , , , ,","place":["Boston, Massachusetts, United States, 02210"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xingyan","family":"Liu","sequence":"additional","affiliation":[{"name":"Eli Lilly and Company , , , ,","place":["Boston, Massachusetts, United States, 02210"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hao-Cheng","family":"Chueh","sequence":"additional","affiliation":[{"name":"Eli Lilly and Company , , , ,","place":["Boston, Massachusetts, United States, 02210"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lujain","family":"Al-Sowaimel","sequence":"additional","affiliation":[{"name":"Eli Lilly and Company , , , ,","place":["Boston, Massachusetts, United States, 02210"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhefeng","family":"Li","sequence":"additional","affiliation":[{"name":"Eli Lilly and Company , , , ,","place":["Boston, Massachusetts, United States, 02210"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claire","family":"Moront","sequence":"additional","affiliation":[{"name":"Eli Lilly and Company , , , ,","place":["Boston, Massachusetts, United States, 02210"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maddie","family":"Carlini","sequence":"additional","affiliation":[{"name":"Eli Lilly and Company , , , ,","place":["Boston, Massachusetts, United States, 02210"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samantha","family":"Sarett","sequence":"additional","affiliation":[{"name":"Eli Lilly and Company , , , ,","place":["Boston, Massachusetts, United States, 02210"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Scott","family":"Brown","sequence":"additional","affiliation":[{"name":"Eli Lilly and Company , , , ,","place":["Boston, Massachusetts, United States, 02210"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0663-6734","authenticated-orcid":true,"given":"Michelle Lynn","family":"Hall","sequence":"additional","affiliation":[{"name":"Eli Lilly and Company , , , ,","place":["Boston, Massachusetts, United States, 02210"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,9,27]]},"reference":[{"key":"2026101210514945100_cit1","unstructured":"QALSODYTM (tofersen)\n          \n          Official HCP Site. https:\/\/www.qalsodyhcp.com\/en-us\/home.html (accessed 2026-08-11)."},{"key":"2026101210514945100_cit2","unstructured":"Official HCP Homepage: SPINRAZA (Nusinersen) HCP. https:\/\/www.spinrazahcp.com\/en_us\/home.html (accessed 2026-08-11)."},{"issue":"6","key":"2026101210514945100_cit3","doi-asserted-by":"publisher","first-page":"524","DOI":"10.1016\/j.molmed.2021.03.010","article-title":"Adeno-Associated Virus Vector for Central Nervous System Gene Therapy","volume":"27","author":"Zhu","year":"2021","journal-title":"Trends Mol. 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